Optimal health outcomes for people living with HIV often depend on orchestrating behavioral changes at many levels, including adhering to antiretroviral regimens, reducing alcohol and drug use, engaging in protective sex and drug-related behaviors, and keeping healthy exercise, smoking, and dietary habits. Any of these behaviors represents a challenge on its own, proof of which is the finding that behavioral interventions have small to moderate effects in all of these domains. The challenge of simultaneously changing all of these behaviors is even greater, but the potential for revolutionary advances is also unsurpassed. We argue that the science of multiple-behavior interventions must include a comprehensive rationale that informs the combinations of behaviors that maximize behavioral, clinical, and economic outcomes while minimizing iatrogenic effects. The project is expected to yield a comprehensive understanding of multiple behavior change and techniques to achieve it, an interactive website for researchers to use the data, and decision trees to derive combinatorial recommendations for different populations, facilitators, geographic areas, disease prevalence contexts, and delivery settings. This application requests funding to decode the best ways of changing multiple behaviors by taking into account that some behavior combinations or couplings are more likely to be synergistic than others. Given the unfeasibility, times, and costs of combining behaviors in all four target domains (e.g., over 20 behaviors) within a randomized controlled trial, we propose to meta-analyze the behavioral and clinical outcomes of interventions that address at least two health behaviors within and across the domains of HIV-related behaviors, drug and alcohol use, and healthy living. Research Synthesis I will concern HIV-specific interventions that explicitly address two or more behaviors (e.g., condom use, number of partners, medication adherence, and drug use during sex). Research Synthesis II will consider interventions to change multiple alcohol/drug use behaviors (e.g., alcohol use and adherence to methadone treatment). Research Synthesis III will consider interventions to change multiple healthy-lifestyle behaviors (e.g., fat intake, exercise, and smoking). Research Synthesis IV will reach broader conclusions across the domains addressed in Syntheses I-III. The project will be the most ambitious meta-analysis in the area of HIV, and will provide data-driven and theory-based estimates of comparative efficacy and effectiveness, stratified by different genders, different racial groups, different continents, and areas of high and low disease prevalence. Given its breadth, our project will be significant to the prevention and treatment of HIV as well as many other diseases related to our clusters of behaviors, including cancer, cardiovascular disease, and diabetes, among others. In addition, our project will advance the psychological understanding of early and delayed behavior change and the design of behavioral interventions addressing complex behaviors. The novelty of the project stems from a transformative theory, obtaining previously inexistent data, refined statistical methods, and pairing meta- analysis and effectiveness research in unprecedented ways. PUBLIC HEALTH RELEVANCE: When current interventions are designed without an understanding of how to optimally mesh behavior recommendations, a theory and evidence-based-intervention principles are likely to catalyze a transformation. Specifically, researching this strikingly uncharted territory has the promise to revolutionize behavioral treatment of HIV as well as other diseases from cancer to cardiovascular disease to diabetes.